Sulfonyldihydroimidazopyridinone compounds as 5-hydroxytryptamine-6 ligands

ABSTRACT

The present invention provides a compound of formula I and the use thereof in the therapeutic treatment of a central nervous system disorder related to or affected by the 5-HT6 receptor.

This application claims the benefit under 35 U.S.C. §119(e) toco-pending U.S. provisional application No. 60/489416, filed Jul. 23,2003, which is hereby incorporated by reference in its entirety.

BACKGROUND OF THE INVENTION

Serotonin (5-Hydroxytryptamine)(5-HT) receptors play a critical role inmany physiological and behavioral functions in humans and animals. Thesefunctions are mediated through various 5-HT receptors distributedthroughout the body. There are now approximately fifteen different human5-HT receptor subtypes that have been cloned, many with well-definedroles in humans. One of the most recently identified 5-HT receptorsubtypes is the 5-HT6 receptor, first cloned from rat tissue in 1993(Monsma, F. J.; Shen, Y.; Ward, R. P.; Hamblin, M. W. MolecularPharmacology 1993, 43, 320-327) and subsequently from human tissue(Kohen, R.; Metcalf, M. A.; Khan, N.; Druck, T.; Huebner, K.; Sibley, D.R. Journal of Neurochemistry 1996, 66, 47-56). The receptor is aG-protein coupled receptor (GPCR) positively coupled to adenylatecyclase (Ruat, M.; Traiffort, E.; Arrang, J-M.; Tardivel-Lacombe, L.;Diaz, L.; Leurs, R.; Schwartz, J-C. Biochemical Biophysical ResearchCommunications 1993, 193, 268-276). The receptor is found almostexclusively in the central nervous system (CNS) areas both in rat and inhuman. In situ hybridization studies of the 5-HT6 receptor in rat brainusing mRNA indicate principal localization in the areas of 5-HTprojection including striatum, nucleus accumbens, olfactory tubercle,and hippocampal formation (Ward, R. P.; Hamblin, M. W. ; Lachowicz, J.E.; Hoffman, B. J.; Sibley, D. R.; Dorsa, D. M. Neuroscience 1995, 64,1105-1111).

There are many potential therapeutic uses for 5-HT6 ligands in humansbased on direct effects and on indications from available scientificstudies. These studies include the localization of the receptor, theaffinity of ligands with known in vivo activity, and various animalstudies conducted so far.

One potential therapeutic use of modulators of 5-HT6 receptor functionis in the enhancement of cognition and memory in human diseases such asAlzheimer's. The high levels of receptor found in important structuresin the forebrain, including the caudate/putamen, hippocampus, nucleusaccumbens, and cortex suggest a role for the receptor in memory andcognition since these areas are known to play a vital role in memory(Gerard, C.; Martres, M.-P.; Lefevre, K.; Miquel, M. C.; Verge, D.;Lanfumey, R.; Doucet, E.; Hamon, M.; El Mestikawy, S. Brain Research,1997, 746, 207-219). The ability of known 5-HT6 receptor ligands toenhance cholinergic transmission also supported the potential cognitionuse (Bentley, J. C.; Boursson, A.; Boess, F. G.; Kone, F. C.; Marsden,C. A.; Petit, N.; Sleight, A. J. British Journal of Pharmacology, 1999,126(7),1537-1542). Studies have found that a known 5-HT6 selectiveantagonist significantly increased glutamate and aspartate levels in thefrontal cortex without elevating levels of noradrenaline, dopamine, or5-HT. This selective elevation of neurochemicals known to be involved inmemory and cognition strongly suggests a role for 5-HT6 ligands incognition (Dawson, L. A.; Nguyen, H. Q.; Li, P. British Journal ofPharmacology, 2000, 130(1), 23-26). Animal studies of memory andlearning with a known selective 5-HT6 antagonist have found positiveindications (Rogers, D. C.; Hatcher, P. D.; Hagan, J. J., Society ofNeuroscience, Abstracts 2000, 26, 680 and Foley, A. G. et al,Neuropsychopharmacology, 2004, 29(1), 93-100).

A related poten

A related therapeutic use for 5-HT6 ligands is the treatment ofattention deficit disorders (ADD, also known as Attention DeficitHyperactivity Disorder or ADHD) in both children and adults. Because5-HT6 antagonists appear to enhance the activity of the nigrostriataldopamine pathway and because ADHD has been linked to abnormalities inthe caudate (Ernst, M; Zametkin, A. J.; Matochik, J. H.; Jons, P. A.;Cohen, R. M. Joumal of Neuroscience 1998, 18(15), 5901-5907), 5-HT6antagonists may attenuate attention deficit disorders.

Early studies examining the affinity of various CNS ligands with knowntherapeutic utility or a strong structural resemblance to known drugssuggests a role for 5-HT6 ligands in the treatment of schizophrenia anddepression. For example, clozapine (an effective clinical antipsychotic)has high affinity for the 5-HT6 receptor subtype. Also, several clinicalantidepressants have high affinity for the receptor as well and act asantagonists at this site (Branchek, T. A.; Blackburn, T. P. AnnualReviews in Pharmacology and Toxicology 2000, 40, 319-334).

Further, recent in vivo studies in rats indicate 5-HT6 modulators may beuseful in the treatment of movement disorders including epilepsy (Stean,T.; Routledge, C.; Upton, N. British Journal of Pharmacology 1999, 127Proc. Supplement 131 P and Routledge, C.; Bromidge, S. M.; Moss, S. F.;Price, G. W.; Hirst, W.; Newman, H.; Riley, G.; Gager, T.; Stean, T.;Upton, N.; Clarke, S. E.; Brown, A. M. British Journal of Pharmacology2000, 130(7), 1606-1612).

Taken together, the above studies strongly suggest that compounds whichare 5-HT6 receptor modulators, i.e. ligands, may be useful fortherapeutic indications including: the treatment of diseases associatedwith a deficit in memory, cognition, and learning such as Alzheimer'sand attention deficit disorder; the treatment of personality disorderssuch as schizophrenia; the treatment of behavioral disorders, e.g.,anxiety, depression and obsessive compulsive disorders; the treatment ofmotion or motor disorders such as Parkinson's disease and epilepsy; thetreatment of diseases associated with neurodegeneration such as strokeand head trauma; or withdrawal from drug addiction including addictionto nicotine, alcohol, and other substances of abuse.

Therefore, it is an object of this invention to provide compounds whichare useful as therapeutic agents in the treatment of a variety ofcentral nervous system disorders related to or affected by the 5-HT6receptor.

It is another object of this invention to provide therapeutic methodsand pharmaceutical compositions useful for the treatment of centralnervous system disorders related to or affected by the 5-HT6 receptor.

It is a feature of this invention that the compounds provided may alsobe used to further study and elucidate the 5-HT6 receptor.

SUMMARY OF THE INVENTION

The present invention provides a compound of formula I

wherein

-   -   Q is —(CR₂R₃)_(n)—NR₄R₅,    -   W is CR₁ or N;    -   X is CR₇ or N;    -   Y is CR₈ or N;    -   Z is CR₉ or N with the proviso that at least one and no more        than two of W, X, Y or Z is N;    -   R is an optionally substituted C₃-C₇ cycloalkyl, aryl or        heteroaryl group or an optionally substituted 8- to 13-membered        bicyclic or tricyclic ring system having a N atom at the        bridgehead and optionally containing 1, 2 or 3 additional        heteroatoms selected from N, O or S;    -   R₁, R₇, R₈ and R₉ are each independently H, halogen, CN,        OCO₂R₁₀, CO₂R₁₁, CONR₁₂R₁₃, SO_(x)R₁₄, NR₁₅R₁₆, OR₁₇, COR₁₈ or a        C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, aryl or        heteroaryl group each optionally substituted;    -   x is 0 or an integer of 1, 2 or 3;    -   R₂ and R₃ are each independently H or an optionally substituted        C₁-C₆alkyl group;    -   n is an integer of 2, 3, 4 or 5;    -   p is 0 or an integer of 1 or 2;    -   R₄ and R₅ are each independently H or a C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl,        aryl or heteroaryl group each optionally substituted or R₄ and        R₅ may be taken together with the atom to which they are        attached to form an optionally substituted 5- to 8-membered ring        optionally containing an additional heteroatom selected from 0,        NR₁₉ or SO_(x);    -   R₆, R₁₉, R₂₀ and R₂₁ are each independently H or a C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl,        aryl, or heteroaryl group each optionally substituted;    -   R₁₀, R₁₁, R₁₄, R₁₇ and R₁₈ are each independently H or a        C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,        cycloheteroalkyl, aryl or heteroaryl group each optionally        substituted;    -   R₁₂ and R₁₃ are each independently H or an optionally        substituted C₁-C₆alkyl group or R₁₂ and R₁₃ may be taken        together with the atom to which they are attached to form a 5-        to 7-membered ring optionally containing another heteroatom        selected from O, NR₂₀ or SO_(x);    -   R₁₅ and R₁₆ are each independently H or an optionally        substituted C₁-C₄alkyl group or R₁₅ and R₁₆ may be taken        together with the atom to which they are attached to form a 5-        to 7-membered ring optionally containing another heteroatom        selected from O, NR₂₁ or SO_(x); and    -   represents a single bond or a double bond; or        a stereoisomer thereof or a pharmaceutically acceptable salt        thereof.

The present invention also provides methods and compositions useful inthe treatment of central nervous system disorders.

DETAILED DESCRIPTION OF THE INVENTION

The 5-hydroxytryptamine-6 (5-HT6) receptor is one of the most recentreceptors to be identified by molecular cloning. Its ability to bind awide range of therapeutic compounds used in psychiatry, coupled with itsintriguing distribution in the brain has stimulated significant interestin new compounds which are capable of interacting with or affecting saidreceptor. Significant efforts are being made to understand the possiblerole of the 5-HT6 receptor in psychiatry, cognitive dysfunction, motorfunction and control, memory, mood and the like. To that end, compoundswhich demonstrate a binding affinity for the 5-HT6 receptor areearnestly sought both as an aid in the study of the 5-HT6 receptor andas potential therapeutic agents in the treatment of central nervoussystem disorders, for example see C. Reavill and D. C. Rogers, CurrentOpinion in Investigational Drugs, 2001, 2(1):104-109, Pharma Press Ltd.

Surprisingly, it has now been found thatsulfonyldihydroimidazopyridinone compounds of formula I demonstrate5-HT6 affinity along with significant sub-type selectivity.Advantageously, said formula I compounds are effective therapeuticagents for the treatment of central nervous system (CNS) disordersassociated with or affected by the 5-HT6 receptor. Accordingly, thepresent invention provides sulfonyldihydroimidazopyridinone compounds offormula I

wherein

-   -   Q is —(CR₂R₃)_(n)—NR₄R₅,    -   W is CR₁ or N;    -   X is CR₇ or N;    -   Y is CR₈ or N;    -   Z is CR₉ or N with the proviso that at least one and no more        than two of W, X, Y or Z is N;    -   R is an optionally substituted C₁-C₆ alkyl, C₃-C₇ cycloalkyl,        aryl or heteroaryl group or an optionally substituted 8- to        13-membered bicyclic or tricyclic ring system having a N atom at        the bridgehead and optionally containing 1, 2 or 3 additional        heteroatoms selected from N, O or S;    -   R₁, R₇, R₈ and R₉ are each independently H, halogen, CN,        OCO₂R₁₀, CO₂R₁₁, CONR₁₂R₁₃, SO_(x)R₁₄, NR₁₅R₁₆, OR₁₇, COR₁₈ or a        C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, aryl or        heteroaryl group each optionally substituted;    -   x is 0 or an integer of 1, 2 or 3;    -   R₂ and R₃ are each independently H or an optionally substituted        C₁-C₆alkyl group;    -   n is an integer of 2, 3, 4 or 5;    -   p is 0 or an integer of 1 or 2;    -   R₄ and R₅ are each independently H or a C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl,        aryl or heteroaryl group each optionally substituted or R₄ and        R₅ may be taken together with the atom to which they are        attached to form an optionally substituted 5- to 8-membered ring        optionally containing an additional heteroatom selected from O,        NR₁₉ or SO_(x);    -   R₆, R₁₉, R₂₀ and R₂₁ are each independently H or a C₁-C₆alkyl,        C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl,        aryl, or heteroaryl group each optionally substituted;    -   R₁₀, R₁₁, R₁₄, R₁₇ and R₁₈ are each independently H or a        C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,        cycloheteroalkyl, aryl or heteroaryl group each optionally        substituted;    -   R₁₂ and R₁₃ are each independently H or an optionally        substituted C₁-C₆alkyl group or R₁₂ and R₁₃ may be taken        together with the atom to which they are attached to form a 5-        to 7-membered ring optionally containing another heteroatom        selected from O, NR₂₀ or SO_(x);    -   R₁₅ and R₁₆ are each independently H or an optionally        substituted C₁-C₄alkyl group or R₁₅ and R₁₆ may be taken        together with the atom to which they are attached to form a 5-        to 7-membered ring optionally containing another heteroatom        selected from O, NR₂₁ or SO_(x); and    -   represents a single bond or a double bond; or        a stereoisomer thereof or a pharmaceutically acceptable salt        thereof.

As used in the specification and claims, the term halogen designates F,Cl, Br or I and the term cycloheteroalkyl designates a five- toseven-membered cycloalkyl ring system containing 1 or 2 heteroatoms,which may be the same or different, selected from N, O or S andoptionally containing one double bond. Exemplary of the cycloheteroalkylring systems included in the term as designated herein are the followingrings wherein X′ is NR′, O or S; and R′ is H or an optional substituentas described hereinbelow:

Similarly, as used in the specification and claims, the term heteroaryldesignates a five- to ten-membered aromatic ring system containing 1, 2or 3 heteroatoms, which may be the same or different, selected from N, Oor S. Such heteroaryl ring systems include pyrrolyl, azolyl, oxazolyl,thiazolyl, imidazolyl, furyl, thienyl, quinolinyl, isoquinolinyl,indolyl, benzothienyl, benzofuranyl, benzisoxazolyl or the like. Theterm aryl designates a carbocyclic aromatic ring system such as phenyl,naphthyl, anthracenyl or the like. The term haloalkyl as used hereindesignates a C_(n)H_(2n−1) group having from one to 2n+1 halogen atomswhich may be the same or different and the term haloalkoxy as usedherein designates an OC_(n)H_(2n+1) group having from one to 2n+1halogen atoms which may be the same or different.

Exemplary of the 8- to 13-membered bicyclic or tricyclic ring systemshaving a N atom at the bridgehead and optionally containing 1, 2 or 3additional heteroatoms selected from N, O or S included in the term asdesignated herein are the following ring systems wherein W′ is NR′, O orS; and R′ is H or an optional substituent as described hereinbelow:

In the specification and claims, when the terms C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl, aryl orheteroaryl are designated as being optionally substituted, thesubstituent groups which are optionally present may be one or more ofthose customarily employed in the development of pharmaceuticalcompounds, or the modification of such compounds, to influence theirstructure/activity, persistence, absorption, stability or otherbeneficial property. Specific examples of such substituents includehalogen atoms, nitro, cyano, thiocyanato, cyanato, hydroxyl, alkyl,haloalkyl, alkoxy, haloalkoxy, amino, alkylamino, dialkylamino, formyl,alkoxycarbonyl, carboxyl, alkanoyl, alkylthio, alkylsuphinyl,alkylsulphonyl, carbamoyl, alkylaminocarbonyl, phenyl, phenoxy, benzyl,benzyloxy, heteroaryl, indolyl, heterocyclyl or cycloalkyl groups,preferably halogen atoms or lower alkyl or lower alkoxy groups.Typically, 0-3 substituents may be present. When any of the foregoingsubstituents represents or contains an alkyl substituent group, this maybe linear or branched and may contain up to 12, preferably up to 6, morepreferably up to 4 carbon atoms.

Pharmaceutically acceptable salts may be any acid addition salt formedby a compound of formula I and a pharmaceutically acceptable acid suchas phosphoric, sulfuric, hydrochloric, hydrobromic, citric, maleic,malonic, mandelic, succinic, fumaric, acetic, lactic, nitric, sulfonic,p-toluene sulfonic, methane sulfonic acid or the like.

Compounds of the invention include esters, carbamates or otherconventional prodrug forms, which in general, are functional derivativesof the compounds of the invention and which are readily converted to theinventive active moiety in vivo. Correspondingly, the method of theinvention embraces the treatment of the various conditions describedhereinabove with a compound of formula I or with a compound which is notspecifically disclosed but which, upon administration, converts to acompound of formula I in vivo. Also included are metabolites of thecompounds of the present invention defined as active species producedupon introduction of these compounds into a biological system.

Compounds of the invention may exist as one or more stereoisomers. Thevarious stereoisomers include enantiomers, diastereomers, atropisomersand geometric isomers. One skilled in the art will appreciate that onestereoisomer may be more active or may exhibit beneficial effects whenenriched relative to the other stereoisomer(s) or when separated fromthe other stereoisomer(s). Additionally, the skilled artisan knows howto separate, enrich or selectively prepare said stereoisomers.Accordingly, the present invention comprises compounds of formula I, thestereoisomers thereof and the pharmaceutically acceptable salts thereof.The compounds of the invention may be present as a mixture ofstereoisomers, individual stereoisomers, or as an optically active orenantiomerically pure form.

Preferred compounds of the invention are those compounds of formula Iwherein R is an optionally substituted aryl or heteroaryl group or anoptionally substituted 8- to 13-membered bicyclic or tricyclic ringsystem having a N atom at the bridgehead and optionally containing 1, 2or 3 additional heteroatoms selected from N, O or S. Another group ofpreferred compounds of the invention are those formula I compoundswherein Q is —(CR₂R₃)_(n)—NR₄R₅ or

Also preferred are those compounds of formula I wherein W is N; X isCR₇; Y is CR₈ and Z is CR₉.

More preferred compounds of the invention are those compounds of formulaI wherein R is an optionally substituted phenyl, naphthyl, thienyl, orimidazo-[2,1-b]-[1,3] thiazolyl group. Another group of more preferredcompounds of formula I are those compounds wherein Q is —CH₂CH₂—NR₄R₅ or

Among the preferred compounds of the invention are:

-   -   3-[2-(dimethylamino)ethyl]-1-[(3-fluorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   1-[(2-chloroimidazo[2,1-b]pyridin-3-yl)sulfonyl]-3-[2-(dimethylamino)ethyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-3-[2-(dimethylamino)ethyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   1-[(3-bromophenyl)sulfonyl]-3-[2-(dimethylamino)ethyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   3-[2-(dimethylamino)ethyl]-1-(thien-2-ylsulfonyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   3-(2-aminoethyl)-1-(phenylsulfonyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   3-(2-aminoethyl)-1-[(3-chlorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   3-(2-aminoethyl)-1-[(5-chlorothien-2-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridi2-one;    -   3-(2-aminoethyl)-1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1,3-dihydro[4,5-b]pyridin-2-one;    -   3-(2-aminoethyl)-1-(2-naphthylsulfonyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   3-(2-aminoethyl)-1-[(3-methoxyphenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   3-(2-aminoethyl)-1-[(2-fluorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2one;    -   3-(2-aminoethyl)-1-[(3-fluorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   3-(2-aminoethyl)-1-[(2-chlorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   3-(2-aminoethyl)-1-[(4-chlorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   3-(2-aminoethyl)-1-[(2,3-dichlorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   3-(2-aminoethyl)-1-[(3-bromophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   3-(2-aminoethyl)-1-[(5-bromothien-2-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   3-(2-aminoethyl)-1-[(2,5-dichlorothien-3-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   1-(2-aminoethyl)-3-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;    -   3-(2-aminoethyl)-1-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;    -   1-(2-aminoethyl)-3-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   1-(2-aminoethyl)-3-[(naphth-1-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;    -   3-phenylsulfonyl-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;    -   1-phenylsulfonyl-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;    -   3-phenylsulfonyl-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;    -   a stereoisomer thereof; and    -   a pharmaceutically acceptable salt thereof.

Advantageously, the present invention provides a process for thepreparation of a compound of formula I which comprises reacting acompound of formula 11 with a sulfonyl chloride, ClSO₂—R, in thepresence of a base. The process is shown in flow diagram I.

Bases suitable for use in the process of the invention include basessuch as NaH, KOt-Bu, diisopropylethylamine, or any conventional basecapable of removing a proton from a nitrogen atom.

Compounds of formula II may be prepared using conventional syntheticmethods and, if required, standard separation or isolation techniques.For example, compounds of formula II may be readily prepared by reactingan ortho-halonitro-pyridine of formula III with the appropriate amine offormula IV to give the corresponding nitro compound of formula V;reducing said formula V compound using a suitable reducing agent such asSnCl₂, or hydrazine and Raney-Nickel or catalytic hydrogenation to givethe diamine of formula VI; and cyclizing said formula VI compound with1,1′-carbonyldiimidazole (CDI) to give the desired formula II compound.The reaction is shown in flow diagram II wherein Hal is Cl or F.

When the formula IV compound contains a Q group having a basic nitrogenatom, for example when Q is 4-piperidinyl, then said formula IV compoundmay be protected prior to the reaction shown in flow diagram I andoptionally deprotected following sulfonylation.

Protecting groups suitable for use in the reactions shown hereinaboveinclude t-butyloxycarbonyl, benzyl, acetyl, benzyloxycarbonyl, or anyconventional group known to protect a basic nitrogen in standardsynthetic procedures.

Advantageously, the formula I compounds of the invention are useful forthe treatment of CNS disorders relating to or affected by the 5-HT6receptor including mood, personality, behavioral, psychiatric,cognitive, neurodegenerative, or the like disorders, for exampleAlzheimer's disease, Parkinson's disease, attention deficit disorder,anxiety, epilepsy, depression, obsessive compulsive disorder, sleepdisorders, neurodegenerative disorders (such as head trauma or stroke),feeding disorders (such as anorexia or bulimia), schizophrenia, memoryloss, disorders associated with withdrawal from drug or nicotine abuse,or the like or certain gastrointestinal disorders such as irritablebowel syndrome. Accordingly, the present invention provides a method forthe treatment of a disorder of the central nervous system related to oraffected by the 5-HT6 receptor in a patient in need thereof whichcomprises providing said patient a therapeutically effective amount of acompound of formula I as described hereinabove. The compounds may beprovided by oral or parenteral administration or in any common mannerknown to be an effective administration of a therapeutic agent to apatient in need thereof.

The term “providing” as used herein with respect to providing a compoundor substance embraced by the invention, designates either directlyadministering such a compound or substance, or administering a prodrug,derivative or analog which forms an equivalent amount of the compound orsubstance within the body.

The therapeutically effective amount provided in the treatment of aspecific CNS disorder may vary according to the specific condition(s)being treated, the size, age and response pattern of the patient, theseverity of the disorder, the judgment of the attending physician or thelike. In general, effective amounts for daily oral administration may beabout 0.01 to 1,000 mg/kg, preferably about 0.5 to 500 mg/kg andeffective amounts for parenteral administration may be about 0.1 to 100mg/kg, preferably about 0.5 to 50 mg/kg.

In actual practice, the compounds of the invention are provided byadministering the compound or a precursor thereof in a solid or liquidform, either neat or in combination with one or more conventionalpharmaceutical carriers or excipients. Accordingly, the presentinvention provides a pharmaceutical composition which comprises apharmaceutically acceptable carrier and an effective amount of acompound of formula I as described hereinabove.

Solid carriers suitable for use in the composition of the inventioninclude one or more substances which may also act as flavoring agents,lubricants, solubilizers, suspending agents, fillers, glidants,compression aides, binders, tablet-disintegrating agents orencapsulating materials. In powders, the carrier may be a finely dividedsolid which is in admixture with a finely divided compound of formula I.In tablets, the formula I compound may be mixed with a carrier havingthe necessary compression properties in suitable proportions andcompacted in the shape and size desired. Said powders and tablets maycontain up to 99% by weight of the formula I compound. Solid carrierssuitable for use in the composition of the invention include calciumphosphate, magnesium stearate, talc, sugars, lactose, dextrin, starch,gelatin, cellulose, methyl cellulose, sodium carboxymethyl cellulose,polyvinylpyrrolidine, low melting waxes and ion exchange resins.

Any pharmaceutically acceptable liquid carrier suitable for preparingsolutions, suspensions, emulsions, syrups and elixirs may be employed inthe composition of the invention. Compounds of formula I may bedissolved or suspended in a pharmaceutically acceptable liquid carriersuch as water, an organic solvent, or a pharmaceutically acceptable oilor fat, or a mixture thereof. Said liquid composition may contain othersuitable pharmaceutical additives such as solubilizers, emulsifiers,buffers, preservatives, sweeteners, flavoring agents, suspending agents,thickening agents, coloring agents, viscosity regulators, stabilizers,osmo-regulators, or the like. Examples of liquid carriers suitable fororal and parenteral administration include water (particularlycontaining additives as above, e.g., cellulose derivatives, preferablysodium carboxymethyl cellulose solution), alcohols (including monohydricalcohols and polyhydric alcohols, e.g., glycols) or their derivatives,or oils (e.g., fractionated coconut oil and arachis oil). For parenteraladministration the carrier may also be an oily ester such as ethyloleate or isopropyl myristate.

Compositions of the invention which are sterile solutions or suspensionsare suitable for intramuscular, intraperitoneal or subcutaneousinjection. Sterile solutions may also be administered intravenously.Inventive compositions suitable for oral administration may be in eitherliquid or solid composition form.

For a more clear understanding, and in order to illustrate the inventionmore clearly, specific examples thereof are set forth hereinbelow. Thefollowing examples are merely illustrative and are not to be understoodas limiting the scope and underlying principles of the invention in anyway.

Unless otherwise stated, all parts are parts by volume. The term NMRdesignates nuclear magnetic resonance. The terms HPLC and TLC designatehigh performance liquid chromatography and thin layer chromatography,respectively. The terms THF, DMF and EtOAc designate tetrahydrofuran,dimethyl formamide and ethyl acetate, respectively.

EXAMPLE 1 Preparation ofN,N-Dimethyl-N′-(3-nitropyrid-2-yl)ethane-1,2-diamine

A solution of 2-chloro-3-nitropyridine (1.76 g, 20.0 mmol) in ethanol istreated with Me₂NCH₂CH₂NH₂ (3.17 g, 20.0 mmol), stirred at ambienttemperature for 17 h, heated to reflux temperature for 7 h, cooled toroom temperature and concentrated in vacuo. The resulting solid residueis triturated with ethanol and suction filtered. The filtercake isair-dried to give the title compound as a yellow solid, 3.20 g (61%yield),. mp 202-203° C., identified by NMR and mass spectral analyses.

EXAMPLE 2 Preparation of N-[2-(Dimethylamino)ethyl]pyridine-2,3-diamine

A heterogeneous mixture ofN,N-dimethyl-N′-2-(3-nitropyridin-2-yl)ethane-1,2-diamine (2.96 g, 12.0mmol) in ethanol is treated with 10% palladium on carbon (0.50 g) andsubjected to 55 psi hydrogen on a Parr apparatus for 22 h. The reactionis suction filtered through Celite. The filtrate is concentrated invacuo to afford a brown oil (ca. 2.5 g). A portion (˜1.5 g) of the oilis chromatographed using 10:90 conc. NH₄OH:ethanol as eluent to affordthe title compound as a brown oil, 1.49 g, identified by NMR.

EXAMPLE 3 Preparation of3-(2-dimethylaminoethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A solution of N-[2-(dimethylamino)ethyl]pyridine-2,3-diamine (1.49 g,8.3 mmol) in DMF is treated with carbonyldiimidazole (CDI) (2.01 g, 12.4g) under nitrogen, stirred at 75-80° C. for 24 h, cooled to roomtemperature and concentrated in vacuo. The resultant residue ischromatographed, eluting with 10:90 conc. NH₄OH:ethanol to afford asolid which is triturated with ethanol:ethyl acetate to afford the titlecompound as a tan solid, 0.387 g, mp 141-142° C., identified by NMR andmass spectral analyses.

EXAMPLE 4 Preparation of3-(2-dimethylaminoethyl)-1-[(3-fluorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A solution of3-(2-dimethylaminoethyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one (20mg, 0.10 mmol) in THF at room temperature is treated with3-fluorophenyl-sulfonyl chloride (26 mg, 0.12 mmol), followed bydiisopropylethylamine (25 μL, 0.20 mmol) and DMAP (5 mg), stirred atroom temperature for 12 h and concentrated in vacuo. The resultantresidue is dissolved in a mixture of DMSO, methanol and water andpurified by Gilson preparative HPLC¹ to give the title compound, [M+H]365, retention time (RT) 2.54 minutes.¹HPLC Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm(i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0mL/min; Solvent A: 0.02% formic acid in water; Solvent B 0.02% formicacid in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sampleconcentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254nm DAD.

EXAMPLES 5-8 Preparation of3-[2-(dimethylamino)ethyl]-1-(arylsulfonyl)-1,3-dihydro-2H-benz-imadazol-2-oneDerivatives

Using essentially the same procedures described in Example 4 hereinaboveand employing the appropriate sulfonyl chloride, the compounds shown inTable I are prepared and identified by HPLC¹ and mass spectral analyses.¹HPLC Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm(i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0mL/min; Solvent A: 0.02% formic acid in water; Solvent B 0.02% formicacid in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sampleconcentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254nm DAD.TABLE I

HPLC Ex. Observed RT No. R Ion (min) 52-chloroimidazo[2,1-b]pyridin-3-yl 423 2.67 [M + H] 62,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl 461 2.82 [M+] 73-bromophenyl 425 2.74 [M+] 8 2-thienyl 353 2.46 [M + H]

EXAMPLE 10 Preparation of N-1-(3-Nitropyrid-2-yl)ethane-1,2-diamine

A mixture of 2-fluoro-3-nitropyridine (8.0 g. 50 mmol) andethylenediamine (3.6 g, 60 mmol) in isopropanol is heated at 100° C. for48 h, cooled to 0° C. and filtered. The filtercake is washed with coldisopropanol and air-dried to afford the title compound as a tan solid,8.5 g, identified by HPLC and mass spectral analyses.

EXAMPLE 11 Preparation of {[2-(3-Nitropyrid-2-yl)amino]ethyl}carbamicacid t-butyl ester

A solution of N-1-(3-nitropyrid-2-yl)ethane-1,2-diamine (2.3 g, 12.7mmol) in 1:1 acetone/water is treated with K₂CO₃ (3.5 g, 25 mmol) anddi-t-butoxydicarbonyl (3.3 g, 15.2 mmol), stirred at room temperaturefor 4 h and concentrated in vacuo to remove the acetone. The aqueousresidue is extracted with EtOAc. The extracts are combined, dried overMgSO₄ and concentrated in vacuo to give the title product as a solid,3.5 g, identified by HPLC and mass spectral anaylses.

EXAMPLE 12 Preparation of {[2-(3-Aminopyrid-2-yl)amino]ethyl}carbamicacid t-butyl ester

A mixture of {[2-(3-nitropyrid-2-yl)amino]ethyl}carbamic acid t-butylester (2.0 g, 7.1 mmol) and Raney-Nickel (0.5 g) in methanol is treateddropwise with hydrazine (0.8 mL, 25 mmol), stirred at room temperaturefor 16 h, treated with Celite and MgSO₄ and filtered. The filtercake iswashed with methanol. The filtrates are combined and concentrated invacuo to afford the title product as a brown oil, 1.8 g, identified byHPLC and mass spectral analyses.

EXAMPLE 13 Preparation of[2-(2-Oxo-2,3-dihydro-2H-imidazor[4,5-b]pyrid-2-yl)ethyl]-carbamic acidt-butyl ester

A mixture of {[2-(3-aminopyrid-2-yl)amino]ethyl}carbamic acid t-butylester (5.04 g, 20 mmol) and carbonyldiimidazole (3.4 g, 22 mmol) in DMFis heated at 110° C. for 16 h, cooled to room temperature and extractedwith EtOAc. The extracts are combined, washed with water, dried overMgSO₄ and concentrated in vacuo. The resultant residue is purified byflash chromatography ( SiO₂, chloroform:methanol: NH₄OH, 90:9:1, aseluent) to give the title compound as a clear oil, 2.9 g, identified byHPLC and mass spectral analyses.

EXAMPLE 14 Preparation of3-(2-Aminoethyl)-1-[(5-chlorothien-2-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one

A solution of[2-(2-oxo-2,3-dihydro-2H-imidazo[4,5-b]pyrid-2-yl)ethyl]-carbamic acidt-butyl ester (27 mg, 0.1 mmol) in THF at room temperature is treatedwith (5-chlorothien-2-yl)sulfonyl chloride (26 mg, 0.12 mmol), followedby diisopropyl-ethylamine (25 μL, 0.2 mmol) and DMAP (5 mg), stirred atroom temperature for 12 h and concentrated in vacuo. The resultantresidue is dissolved in THF, treated with 4 N HCl in dioxane (1 mL),stirred for 8 h and concentrated in vacuo. This residue is dissolved ina mixture of DMSO, methanol and water and purified by Gilson preparativeHPLC¹ to give the title compound, 6 mg, [M+H] 359, retention time (RT)2.04 minutes.¹HPLC Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm(i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0mL/min; Solvent A: 0.02% formic acid in water; Solvent B 0.02% formicacid in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sampleconcentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254nm DAD.

EXAMPLES 15-27 Preparation of3-(2-Aminoethyl)-1-(arylsulfonyl)-1,3-dihydro-2H-imidazo[4,5-b1-pyridin-2-one Derivatives

Using essentially the same procedure described in Example 14 hereinaboveand employing the appropriate arylsulfonyl chloride, the compounds shownin Table II are obtained and identified by HPLC¹ and mass spectralanalyses.¹HPLC Conditions: HP 1100 HPLC system; Waters Xterra MS C18, 2 mm(i.d.)×50 mm (length), 3.5 um column, set at 50° C.; Flow rate 1.0mL/min; Solvent A: 0.02% formic acid in water; Solvent B 0.02% formicacid in ACN; Gradient: Time O: 10% B; 2.5 min 90% B; 3 min 90% B; Sampleconcentration: ˜2.0 mM; Injection volume: 5 uL; Detection: 220 nm, 254nm DAD.TABLE II

Ex. RT No. R Observed Ion (min) 15 phenyl 319 [M + H] 1.82 163-chlorophenyl 353 [M + H] 2.06 176-chloroimidazo[2,1-b][1,3]thiazol-5-yl 399 [M + H] 1.93 18 2-naphthyl369 [M + H] 2.21 19 3-methoxyphenyl 349 [M + H] 1.96 20 2-fluorophenyl337 [M + H] 1.88 21 3-fluorophenyl 337 [M + H] 1.91 22 2-chlorophenyl353 [M + H] 1.97 23 4-chlorophenyl 353 [M + H] 2.06 242,3-dichlorophenyl 387 [M + H] 2.18 25 3-bromophenyl 397 [M + H] 2.1 265-bromothien-2-yl 403 [M + H] 2.08 27 2,5-dichlorothien-3-yl 393 [M + H]2.26

EXAMPLE 28 Comparative Evaluation of 5-HT6 Binding Affinity of TestCompounds

The affinity of test compounds for the serotonin 5-HT6 receptor isevaluated in the following manner. Cultured Hela cells expressing humancloned 5-HT6 receptors are harvested and centrifuged at low speed(1,000×g) for 10.0 min to remove the culture media. The harvested cellsare suspended in half volume of fresh physiological phosphate bufferedsaline solution and recentrifuged at the same speed. This operation isrepeated. The collected cells are then homogenized in ten volumes of 50mM Tris.HCl (pH 7.4) and 0.5 mM EDTA. The homogenate is centrifuged at40,000×g for 30.0 min and the precipitate is collected. The obtainedpellet is resuspended in 10 volumes of Tris.HCl buffer and recentrifugedat the same speed. The final pellet is suspended in a small volume ofTris.HCl buffer and the tissue protein content is determined in aliquotsof 10-25 μl volumes. Bovine Serum Albumin is used as the standard in theprotein determination according to the method described in Lowry et al.,J. Biol. Chem., 193:265 (1951). The volume of the suspended cellmembranes is adjusted to give a tissue protein concentration of 1.0mg/ml of suspension. The prepared membrane suspension (10 timesconcentrated) is aliquoted in 1.0 ml volumes and stored at −70° C. untilused in subsequent binding experiments.

Binding experiments are performed in a 96 well microtiter plate format,in a total volume of 200 μl. To each well is added the followingmixture: 80.0 μl of incubation buffer made in 50 mM Tris.HCl buffer (pH7.4) containing 10.0 mM MgCl₂ and 0.5 mM EDTA and 20 μl of [³H]-LSD(S.A., 86.0 Ci/mmol, available from Amersham Life Science), 3.0 nM. Thedissociation constant, K_(D) of the [³H]LSD at the human serotonin 5-HT6receptor is 2.9 nM, as determined by saturation binding with increasingconcentrations of [³H]LSD. The reaction is initiated by the finaladdition of 100.0 μl of tissue suspension. Nonspecific binding ismeasured in the presence of 10.0 μM methiothepin. The test compounds areadded in 20.0 μl volume.

The reaction is allowed to proceed in the dark for 120 min at roomtemperature, at which time, the bound ligand-receptor complex isfiltered off on a 96 well unifilter with a Packard Filtermate® 196Harvester. The bound complex caught on the filter disk is allowed to airdry and the radioactivity is measured in a Packard TopCount® equippedwith six photomultiplier detectors, after the addition of 40.0 μlMicroscint®-20 scintillant to each shallow well. The unifilter plate isheat-sealed and counted in a PackardTopCount® with a tritium efficiencyof 31.0%.

Specific binding to the 5-HT6 receptor is defined as the totalradioactivity bound less the amount bound in the presence of 10.0 μMunlabeled methiothepin. Binding in the presence of varyingconcentrations of test compound is expressed as a percentage of specificbinding in the absence of test compound. The results are plotted as log% bound versus log concentration of test compound. Nonlinear regressionanalysis of data points with a computer assisted program Prism® yieldedboth the IC₅₀ and the K_(i)values of test compounds with 95% confidencelimits. A linear regression line of data points is plotted, from whichthe IC₅₀ value is determined and the K_(i) value is determined basedupon the following equation:K _(i) =IC ₅₀/(1+L/K _(D))where L is the concentration of the radioactive ligand used and K_(D) isthe dissociation receptor, both expressed in nM.

Using the assay, the following Ki values are determined and compared bythose values obtained by representative compounds known to demonstratebinding tothe 5-HT6 receptor. The data are shown in Table III, below.TABLE III Test Compound 5-HT6 binding Ki (Ex. No.) (nM)  4 80  7 23 1418 15 44 16 16 17 4 18 5 19 14 20 77 22 55 23 17 24 9 25 12 26 9 27 22Comparative Examples 5-HT6 binding Ki Clozapine 6.0 Loxapine 41.4Bromocriptine 23.0 Methiothepin 8.3 Mianserin 44.2 Olanzepine 19.5

1. A compound of formula I

wherein Q is —(CR₂R₃)_(n)—NR₄R₅,

W is CR₁ or N; X is CR₇ or N; Y is CR₈ or N; Z is CR₉ or N with theproviso that at least one and no more than two of W, X, Y or Z is N; Ris an optionally substituted C₃-C₇ cycloalkyl, aryl or heteroaryl groupor an optionally substituted 8- to 13-membered bicyclic or tricyclicring system having a N atom at the bridgehead and optionally containing1, 2 or 3 additional heteroatoms selected from N, O or S; R₁, R₇, R₈ andR₉ are each independently H, halogen, CN, OCO₂R₁₀, CO₂R₁₁, CONR₁₂R₁₃,SO_(x)R₁₄, NR₁₅R₁₆, OR₁₇, COR₁₈ or a C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₇cycloalkyl, aryl or heteroaryl group each optionallysubstituted; x is 0 or an integer of 1, 2 or 3; R₂ and R₃ are eachindependently H or an optionally substituted C₁-C₆alkyl group; n is aninteger of 2, 3, 4 or 5; p is 0 or an integer of 1 or 2; R₄ and R₅ areeach independently H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted or R₄ and R₅ may be taken together with the atomto which they are attached to form an optionally substituted 5- to8-membered ring optionally containing an additional heteroatom selectedfrom O, NR₁₉ or SO_(x); R₆, R₁₉, R₂₀ and R₂₁ are each independently H ora C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl, or heteroaryl group each optionally substituted;R₁₀, R₁₁, R₁₄, R₁₇ and R₁₈ are each independently H or a C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl orheteroaryl group each optionally substituted; R₁₂ and R₁₃ are eachindependently H or an optionally substituted C₁-C₆alkyl group or R₁₂ andR₁₃ may be taken together with the atom to which they are attached toform a 5- to 7-membered ring optionally containing another heteroatomselected from O, NR₂₀ or SO_(x); R₁₅ and R₁₆ are each independently H oran optionally substituted C₁-C₄alkyl group or R₁₅ and R₁₆ may be takentogether with the atom to which they are attached to form a 5- to7-membered ring optionally containing another heteroatom selected fromO, NR₂₁ or SO_(x); and

represents a single bond or a double bond; or a stereoisomer thereof ora pharmaceutically acceptable salt thereof.
 2. The compound according toclaim 1 wherein R is an optionally substituted aryl or heteroaryl groupor an optionally substituted 8- to 13-membered bicyclic or tricyclicring system having a N atom at the bridgehead and optionally containing1, 2 or 3 additional heteroatoms selected from N, O or S.
 3. Thecompound according to claim 1 wherein Q is —(CR₂R₃)_(n)—NR₄R₅ or


4. The compound according to claim 1 wherein W is N; X is CR₇; Y is CR₈and Z is CR₉.
 5. The compound according to claim 2 wherein R is anoptionally substituted phenyl, naphthyl, thienyl orimidazo[2,1-b][1,3]thiazolyl group.
 6. The compound according to claim 3wherein R₂ and R₃ are H; n is an integer of 2; R₆ is H; and p is aninteger of
 1. 7. The compound according to claim 4 wherein R is anoptionally substituted phenyl, naphthyl, thienyl orimidazo[2,1-b][1,3]thiazolyl group.
 8. The compound according to claim 5wherein Q is —CH₂CH₂—NR₄R₅. or


9. The compound according to claim 1 selected from the group consistingof:3-[2-(dimethylamino)ethyl]-1-[(3-fluorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;1-[(2-chloroimidazo[2,1-b]pyridin-3-yl)sulfonyl]-3-[2-(dimethylamino)ethyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-3-[2-(dimethylamino)ethyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;1-[(3-bromophenyl)sulfonyl]-3-[2-(dimethylamino)ethyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-[2-(dimethylamino)ethyl]-1-(thien-2-ylsulfonyl)-1,3-dihydro-2H-imidazo[4,5]pyridin-2-one;3-(2-aminoethyl)-1-(phenylsulfonyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(3-chlorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(5-chlorothien-2-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-(2-naphthylsulfonyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(3-methoxyphenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(2-fluorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(3-fluorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(2-chlorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(4-chlorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(2,3-dichlorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(3-bromophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(5-bromothien-2-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(2,5-dichlorothien-3-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;1-(2-aminoethyl)-3-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;3-(2-aminoethyl)-1-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;1-(2-aminoethyl)-3-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;1-(2-aminoethyl)-3-[(naphth-1-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;3-(2-aminoethyl)-1-[(naphth-1-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;1-(2-aminoethyl)-3-[(naphth-1-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;1-[2-(dimethylamino)ethyl]-3-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;3-[2-(dimethylamino)ethyl]-1-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;1-[2-(dimethylamino)ethyl]-3-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-phenylsulfonyl-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;1-phenylsulfonyl-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;3-phenylsulfonyl-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;a stereoisomer thereof; and a pharmaceutically acceptable salt thereof.10. A method for the treatment of a central nervous system disorderrelated to or affected by the 5-HT6 receptor in a patient in needthereof which comprises providing to said patient a therapeuticallyeffective amount of a compound of formula I

wherein Q is —(CR₂R₃)_(n)—NR₄R₅,

W is CR₁ or N; X is CR₇ or N; Y is CR₈ or N; Z is CR₉ or N with theproviso that at least one and no more than two of W, X, Y or Z is N; Ris an optionally substituted C₁-C₆ alkyl, C₃-C₇ cycloalkyl, aryl orheteroaryl group or an optionally substituted 8- to 13-membered bicyclicor tricyclic ring system having a N atom at the bridgehead andoptionally containing 1, 2 or 3 additional heteroatoms selected from N,O or S; R₁, R₇, R₈ and R₉ are each independently H, halogen, CN,OCO₂R₁₀, CO₂R₁₁, CONR₁₂R₁₃, SO_(x)R₁₄, NR₁₅R₁₆, OR₁₇, COR₁₈ or aC₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, aryl orheteroaryl group each optionally substituted; x is 0 or an integer of 1,2 or 3; R₂ and R₃ are each independently H or an optionally substitutedC₁-C₆alkyl group; n is an integer of 2, 3, 4 or 5; p is 0 or an integerof 1 or 2; R₄ and R₅ are each independently H or a C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₇cycloalkyl, cycloheteroalkyl, aryl orheteroaryl group each optionally substituted or R₄ and R₅ may be takentogether with the atom to which they are attached to form an optionallysubstituted 5- to 8-membered ring optionally containing an additionalheteroatom selected from O, NR₁₉or SO_(x); R₆, R₁₉, R₂₀ and R₂₁ are eachindependently H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, cycloheteroalkyl, aryl, or heteroaryl group eachoptionally substituted; R₁₀, R₁₁, R₁₄, R₁₇ and R₁₈ are eachindependently H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₆cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted; R₁₂ and R₁₃ are each independently H or anoptionally substituted C₁-C₆alkyl group or R₁₂ and R₁₃ may be takentogether with the atom to which they are attached to form a 5- to7-membered ring optionally containing another heteroatom selected fromO, NR₂₀ or SO_(x); R₁₅ and R₁₆ are each independently H or an optionallysubstituted C₁-C₄alkyl group or R₁₅ and R₁₆ may be taken together withthe atom to which they are attached to form a 5- to 7-membered ringoptionally containing another heteroatom selected from O, NR₂₁ orSO_(x); and

represents a single bond or a double bond; or a stereoisomer thereof ora pharmaceutically acceptable salt thereof.
 11. The method according toclaim 10 wherein said disorder is an anxiety disorder or a cognitivedisorder.
 12. The method according to claim 10 wherein said disorder isa neurodegenerative disorder.
 13. The method according to claim 11wherein said disorder is selected from the group consisting of:attention deficit disorder; obsessive compulsive disorder; withdrawalfrom drug, alcohol or nicotine addiction; schizophrenia; depression; andAlzheimer's disease.
 14. The method according to claim 12 wherein saiddisorder is selected from the group consisting of: stroke; head trauma;and neuropathic pain.
 15. A pharmaceutical composition which comprises apharmaceutically acceptable carrier and an effective amount of acompound of formula I

wherein Q is —(CR₂R₃)_(n)—NR₄R₅,

W is CR₁ or N; X is CR₇ or N; Y is CR₈ or N; Z is CR₉ or N with theproviso that at least one and no more than two of W, X, Y or Z is N; Ris an optionally substituted C₃-C₇ cycloalkyl, aryl or heteroaryl groupor an optionally substituted 8- to 13-membered bicyclic or tricyclicring system having a N atom at the bridgehead and optionally containing1, 2 or 3 additional heteroatoms selected from N, O or S; R₁, R₇, R₈ andR₉ are each independently H, halogen, CN, OCO₂R₁₀, CO₂R₁₁, CONR₁₂R₁₃,SO_(x)R₁₄, NR₁₅R₁₆, OR₁₇, COR₁₈ or a C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₇cycloalkyl, aryl or heteroaryl group each optionallysubstituted; x is 0 or an integer of 1, 2 or 3; R₂ and R₃ are eachindependently H or an optionally substituted C₁-C₆alkyl group; n is aninteger of 2, 3, 4 or 5; p is 0 or an integer of 1 or 2; R₄ and R₅ areeach independently H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted or R₄ and R₅ may be taken together with the atomto which they are attached to form an optionally substituted 5- to8-membered ring optionally containing an additional heteroatom selectedfrom O, NR₁₉or SO_(x); R₆, R₁₉, R₂₀ and R₂₁ are each independently H ora C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl, or heteroaryl group each optionally substituted;R₁₀, R₁₁, R₁₄, R₁₇ and R₁₈ are each independently H or a C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl orheteroaryl group each optionally substituted; R₁₂ and R₁₃ are eachindependently H or an optionally substituted C₁-C₆alkyl group or R₁₂ andR₁₃ may be taken together with the atom to which they are attached toform a 5- to 7-membered ring optionally containing another heteroatomselected from O, NR₂₀ or SO_(x); R₁₅ and R₁₆ are each independently H oran optionally substituted C₁-C₄alkyl group or R₁₅ and R₁₆ may be takentogether with the atom to which they are attached to form a 5- to7-membered ring optionally containing another heteroatom selected fromO, NR₂₁ or SO_(x); and

represents a single bond or a double bond; or a stereoisomer thereof ora pharmaceutically acceptable salt thereof.
 16. The compositionaccording to claim 15 having a formula I compound wherein R is anoptionally substituted phenyl, naphthyl, thienyl orimidazo[2,1-b][1,3]-thiazolyl group.
 17. The composition according toclaim 16 having a formula I compound wherein Q is —CH₂CH₂—NR₄R₅;4-piperidinyl or 4-(1,2,3,6-tetrahydropyridinyl).
 18. The compositionaccording to claim 17 having a formula I compound wherein W is N; X isCR₇; Y is CR₈; and Z is CR₉.
 19. The composition according to claim 15having a formula I compound selected from the group consisting of:3-[2-(dimethylamino)ethyl]-1-[(3-fluorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;1-[(2-chloroimidazo[2,1-b]pyridin-3-yl)sulfonyl]-3-[2-(dimethylamino)ethyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;1-[(2,6-dichloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-3-[2-(dimethylamino)ethyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;1-[(3-bromophenyl)sulfonyl]-3-[2-(dimethylamino)ethyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-[2-(dimethylamino)ethyl]-1-(thien-2-ylsulfonyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-(phenylsulfonyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(3-chlorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(5-chlorothien-2-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(6-chloroimidazo[2,1-b][1,3]thiazol-5-yl)sulfonyl]-1,3-dihyidro-2H-imaidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-(2-naphthylsulfonyl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(3-methoxyphenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(2-fluorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(3-fluorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(2-chlorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(4-chlorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(2,3-dichlorophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(3-bromophenyl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(5-bromothien-2-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-(2-aminoethyl)-1-[(2,5-dichlorothien-3-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;1-(2-aminoethyl)-3-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;3-(2-aminoethyl)-1-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;1-(2-aminoethyl)-3-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;1-(2-aminoethyl)-3-[(naphth-1-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;3-(2-aminoethyl)-1-[(naphth-1-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;1-(2-aminoethyl)-3-[(naphth-1-yl)sulfonyl]-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;1-[2-(dimethylamino)ethyl]-3-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;3-[2-(dimethylamino)ethyl]-1-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;1-[2-(dimethylamino)ethyl]-3-phenylsulfonyl-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;3-phenylsulfonyl-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;1-phenylsulfonyl-3-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-c]pyridin-2-one;3-phenylsulfonyl-1-(pyrrolidin-3-yl)-1,3-dihydro-2H-imidazo[4,5-b]pyridin-2-one;a stereoisomer thereof; and a pharmaceutically acceptable salt thereof.20. A process for the preparation of a compound of formula I The presentinvention provides a compound of formula I

wherein Q is —(CR₂R₃)_(n)—NR₄R₅,

W is CR₁ or N; X is CR₇ or N; Y is CR₈ or N; Z is CR₉ or N with theproviso that at least one and no more than two of W, X, Y or Z is N; Ris an optionally substituted C₃-C₇ cycloalkyl, aryl or heteroaryl groupor an optionally substituted 8- to 1 3-membered bicyclic or tricyclicring system having a N atom at the bridgehead and optionally containing1, 2 or 3 additional heteroatoms selected from N, O or S; R₁, R₇, R₈ andR₉ are each independently H, halogen, CN, OCO₂R₁₀, CO₂R₁₁, CONR₁₂R₁₃,SO_(x)R₁₄, NR₁₅R₁₆, OR₁₇, COR₁₈ or a C₁-C₆alkyl, C₂-C₆alkenyl,C₂-C₆alkynyl, C₃-C₇cycloalkyl, aryl or heteroaryl group each optionallysubstituted; x is 0 or an integer of 1, 2 or 3; R₂ and R₃ are eachindependently H or an optionally substituted C₁-C₆alkyl group; n is aninteger of 2, 3, 4 or 5; p is 0 or an integer of 1 or 2; R₄ and R₅ areeach independently H or a C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl,C₃-C₇cycloalkyl, cycloheteroalkyl, aryl or heteroaryl group eachoptionally substituted or R₄ and R₅ may be taken together with the atomto which they are attached to form an optionally substituted 5- to8-membered ring optionally containing an additional heteroatom selectedfrom O, NR₁₉ or SO_(x); R₆, R₁₉, R₂₀ and R₂₁ are each independently H ora C₁-C₆alkyl, C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl,cycloheteroalkyl, aryl, or heteroaryl group each optionally substituted;R₁₀, R₁₁, R₁₄, R₁₇ and R₁₈ are each independently H or a C₁-C₆alkyl,C₂-C₆alkenyl, C₂-C₆alkynyl, C₃-C₆cycloalkyl, cycloheteroalkyl, aryl orheteroaryl group each optionally substituted; R₁₂ and R₁₃ are eachindependently H or an optionally substituted C₁-C₆alkyl group or R₁₂ andR₁₃ may be taken together with the atom to which they are attached toform a 5- to 7-membered ring optionally containing another heteroatomselected from O, NR₂₀ or SO_(x); R₁₅ and R₁₆ are each independently H oran optionally substituted C₁-C₄alkyl group or R₁₅ and R₁₆ may be takentogether with the atom to which they are attached to form a 5- to7-membered ring optionally containing another heteroatom selected fromO, NR₂₁ or SO_(x); and

represents a single bond or a double bond which process comprisesreacting a compound of formula II

wherein Q, W, X, Y and Z are as described hereinabove with a sulfonylchloride, RSO₂Cl, wherein R is described hereinabove in the presence ofa base optionally in the presence of a solvent.